Autoimmune diseases are believed to be induced by the incomplete removal of self-reactive lymphocytes in thymus glands. Among them, rheumatoid arthritis (also referred to as “RA” hereinafter) is a progressive inflammatory disease where joint pain•swelling•inflammation systemically spread for unknown reasons, and subsequently deformity•destruction of joint becomes advanced as these conditions continue, and finally physical disability is triggered. A major pathology of RA is synovium, and synoviocytes that compose synovium are proliferated, which gradually affects the surrounding cartilage•bone to cause destruction and deformity of joint.
IL-17, and IL-15 which induces the same have been confirmed in high concentrations in synovial fluid of RA patients, and have been indicated to be involved in inflammation, bone destruction (Nonpatent document 1). It has been also reported that the incidence of arthritis in IL-17-deficient mice is significantly suppressed compared to wild-type mice in type II collagen-induced arthritis model (Nonpatent document 2), and that the arthritis scores are significantly suppressed when anti-mouse IL-17-neutralizing antibody is prophylactically or therapeutically administered to type II collagen-induced mice arthritis model (Nonpatent document 3), etc. IL-17 also activates synoviocytes and chondrocytes to promote the production of cytokines or chemokines such as IL-1, TNF-γ and osteoclast differentiation factor (RANKL). Further, IL-17 has been considered to be involved in the induction of collagenolytic enzymes from these cells to induce joint destruction (Nonpatent document 4). Accordingly, it is considered that IL-17 is closely involved in the development and progress of rheumatoid arthritis.
In addition to rheumatoid arthritis, it has been recognized that IL-17 was produced or its expression was increased in multiple sclerosis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease, transplantation rejection, asthma, etc. (Nonpatent document 5). It has been also reported that pathogenesis of mouse experimental encephalomyelitis (EAE) in IL-17-deficient mice is significantly suppressed compared to wild-type mice in EAE model (Nonpatent document 6), and inflammation of bowel in IL-17R-deficient mice is also reduced in TNBS-induced mouse enteritis model as well (Nonpatent document 7). Further, each reaction in IL-17-deficient mice was also reduced compared to wild-type mice in trinitrochlorobenzene-induced contact-type hypersensitivity, methylated bovine serum albumin-induced delayed-type hypersensitivity and ovalbumin-induced reactive airway disease (Nonpatent document 8). These facts indicated that IL-17 is also involved in autoimmune diseases and inflammatory/allergic diseases such as multiple sclerosis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease.
Accordingly, it is considered that controlling the production of IL-17 from T cells is useful for a prophylactic and/or therapeutic agent for autoimmune diseases and inflammatory/allergic diseases such as multiple sclerosis, systemic lupus erythematosus, psoriasis, inflammatory bowel disease as well as rheumatoid arthritis.
As mentioned above, it has been indicated that IL-17 generated from T cells is deeply involved in various autoimmune diseases and inflammatory/allergic diseases including rheumatoid arthritis. Hence, it is believed that compounds controlling the production of IL-17 from T cells show remarkable effects on prophylaxis and/or treatment of various autoimmune diseases and inflammatory/allergic diseases.
Cyclosporin has been known as a compound controlling the production of IL-17 (Nonpatent documents 9, 10). Cyclosporin inhibits the activation of calcineurin by forming a complex with intracellular binding protein, cyclophilin. As a result, the intranuclear localization by dephosphorylation of transcription factor NF-AT such as IL-2 is inhibited, and the production of cytokines from T cells is suppressed. As to cyclosporin, therapeutic effects for autoimmune diseases have been already recognized, but side effects such as renal disorder have been seen as a problem. A therapeutic agent for autoimmune diseases with showing more remarkable therapeutic effects and with fewer side effects has been desired especially in RA area, etc. for which prolonged administration is required.
On the other hand, specific amide derivatives with lymphocytic antiproliferative effects have been reported in Nonpatent document 11 and Patent documents 1 to 4, nevertheless, they have different structures from the present invention. In Patent documents 5 to 7, no lymphocytic antiproliferative effects are mentioned, and compounds with different structures from the present invention are reported.